: The goal of this project is to elucidate the function of huntingtin protein, mutation of which underlies Huntington's disease (HD). These mutations are expansions of a polyglutamine repeat motif (coded by CAG trinucleotide repeats in the mRNA) within the protein, making HD one of several known "glutamine repeat disorders". In this group of neurodegenerative diseases, an expansion of a polyglutamine repeat in a number of different proteins confers the various disease phenotypes. However, in spite of the relatively restricted patterns of differential cell death in HD and the other disorders, the gene products are widely distributed in both central nervous system and peripheral tissues, and both their normal functions and mechanisms of disease are largely unknown. This study will examine the function of huntingtin through three specific aims. First, analysis of the interaction between huntingtin and Sp1 will be performed. In our preliminary work, using the yeast two-hybrid system we showed that the N-terminus portion of huntingtin specifically interacts with transcription factor Spl. In this study the effect of expansions of the polyglutamine tract on the strength of Sp1-huntingtin interaction will be assessed. The domains of interaction will be studied by deletional analysis of the respective cDNA's. The effect of huntingtin protein with variable glutamine repeats on transcription will then be determined. Our preliminary results showed that huntingtin and Sp1 synergistically activate the promoter of NMDAR1 subtype of glutamate receptor. To examine the promoter regions involved in Sp1/huntingtin mediated regulation, a deletion analysis and in-vitro mutagenesis of promoter elements and proteins will be employed. Finally, we will attempt to generate a huntingtin dominant-negative construct to alter the activity of NMDAR1 promoter.